IRS, as defined herein, means the concomitant existence in a subject of two or more of: hyperinsulinemia, dyslipidemia, hypertension, type 2 diabetes or impaired glucose tolerance, hyperuricemia or gout, a pro-coagulant state, atherosclerosis and/or truncal obesity. At the center of IRS, also known as “Syndrome X” and “Metabolic Syndrome” in the biomedical literature, is the common feature of tissue resistance to the action of insulin. This impaired biological response to insulin is manifested in the metabolic and vascular effects of insulin. Although there are monogenic syndromes of insulin resistance (IR), in which a definite gene has been identified as the cause of insulin resistance (such as leprechaunism), these are relatively rare. By contrast, the more common presentation of the IRS is associated with obesity (particularly abdominal) and appears to be polygenic.
The adaptive response to IR in individuals having IRS produces compensatory hyperinsulinaemia. As subjects with IRS become progressively insulin resistant, they manifest varying degrees of change in clinical parameters, including blood pressure, and/or increased levels of serum glucose, and/or cholesterol and/or triglycerides, and/or uric acid, and/or factors that increase coagulation. Once these clinical parameters have changed enough, the patient with IRS may differentially manifest well-recognized clinical conditions or diagnoses.                2. These conditions include: type 2 diabetes, hypertension (high blood pressure), hyperlipidemia or dyslipidemia, particularly (but not limited to) hypertriglyceridemia, hyperuricemia or gout, and hypercoagulability (defined as an abnormal, increased tendency for clots to form, particularly inside blood vessels). These clinical conditions are well-recognized risk factors for cardiovascular (coronary artery and cerebrovascular) disease.        
While it is difficult to estimate the prevalence of IRS in the general populace due to both the diversity of the collective risk factors associated with the syndrome and the likelihood that many individuals affected by IRS go undetected because they may exhibit no exterior symptoms and have no prior history of coronary heart disease, it is postulated that at a minimum the patient population at risk for the development of IRS includes individuals with obesity, particularly truncal (abdominal) obesity. Obesity is an extremely common problem in the industrialized world and is associated with the clinical conditions mentioned above. Thus, it is very likely that the prevalence of IRS is very high. Considering this potential patient group alone forms an immense population potentially at risk for the development of complications of IRS. For example in the United States in 1994, 23% of the population aged between 20 and 74 had hypertension, which accounted for 5 deaths per 100,000 population (1997). There will be an estimated 154,392,000 patients with diabetes world-wide in the year 2000. Of these, 15,000,000 will be in the US and 934,000 in the UK. The burden of disease for ischaemic heart disease for both sexes in the WHO region estimated for 1998 was 51,948,000 with a mortality of 7,375,000, constituting 13.7% of total mortality and ranking the highest in the mortality score. The burden of diabetes in both sexes in the WHO region estimated for 1998 was 11,668,000. Thus there exists a large medical need for an effective and safe oral therapy for the treatment of IRS and prevention of the development of IRS and its clinical consequences.
Resistance to the effects of insulin is also observed in the diminished biological response of the endothelium to the vascular effects of insulin. That is, insulin promotes relaxation of blood vessels at least in part through the action of nitric oxide (NO). Nitric oxide generated in the endothelium then stimulates cGMP production in blood vessels and causes them to relax or dilate. This opening of the blood vessel allows more blood to flow, which is particularly important when more blood flow is needed to critical organs, like the heart. It has been demonstrated that there is a decreased release of NO from the endothelium of patients with IR. This decreased release of NO is not only from insulin, but also from other important vasodilators like acetylcholine. This so-called “endothelial dysfunction” contributes to the risk factors for cardiovascular disease which are associated with IRS. The vascular effect of insulin contributes to the effect of insulin to regulate metabolism, particularly, but not necessarily limited to, glucose metabolism.
NO also has direct effects on glucose uptake by skeletal muscle. That is, treatment with a NO-donor substance, such as nitroprusside, or with an analogue of cGMP in vitro increases glucose uptake (transport by GLUT4 glucose transporters). This vasodilation-independent pathway is described in G. J. Etgen, D. A. Fryburg and E. M. Gibbs in Diabetes, 46, 1997 pp. 1915-1919, which is incorporated herein by reference. Taken together, NO and cGMP have direct target tissue (skeletal muscle) and vascular actions that influence, mediate, or mimic the action of insulin.
Further effects of impaired NO release by the endothelium include: increases in vascular smooth muscle cell (VSMC) growth, proliferation and migration which are key steps in atherosclerotic plaque formation that can lead to stroke; an increase in platelet aggregation and adhesiveness; an increase of lipid peroxidation and an effect on the inhibition of cell adhesion molecule expression including vascular cell adhesion molecule (VCAM-1), intracellular adhesion molecule (ICAM), E-selectin. Impaired endothelial NO release also impacts on the activity of inflammatory cytokines such as tumour necrosis factor-α (TNF-α), and the production of monocyte chemoattractant factor through decreased activity of the transcriptional activator nuclear factor kappa B. These effects on the platelet are also cGMP driven.
Finally, there are examples in which the treatment of factors contributing to IRS (e.g., obesity) or the treatment of IRS itself improves many of these clinical conditions which at first glance appear to be unrelated. For example, dieting alone or pharmacotherapeutic agents that induce weight loss will decrease blood pressure, blood glucose and triglycerides. Agents that are designed to improve insulin sensitivity can also favorably alter blood pressure, lipids, and blood glucose.
Successful diagnosis and treatment of patients with IRS with a PDE9 inhibitor will lead to clinically relevant improvements in blood pressure, and/or serum glucose and/or insulin and/or lipids and/or uric acid, and/or procoagulant factors. This treatment can occur alone or in combination with other therapeutics that improve IRS. Improvement in these clinical conditions should reduce the risk of the development of cardiovascular disease in these patients as well as other complications of these individual disorders (including, but not limited to diabetic neuropathy, nephropathy, and retinopathy).
While IRS has many manifestations, an important underlying mechanistic basis for the condition resides in a resistance to both the vascular and metabolic effects of insulin. It is also understood that the underlying pathology of vascular resistance in insulin resistance syndrome, is a diminished amount of NO produced by the endothelial cells in response to insulin. There is impaired signaling of insulin for glucose uptake in insulin resistant individuals.
Amplification of the cGMP signal, using CGMP PDE9 inhibitors in patients with IRS enhances the insulin glucose uptake signal and improves insulin action at key tissues. Enhancing insulin sensitivity improves clinical parameters of IRS results, inter alia, in:                1. Blood glucose control: In patients with type 2 diabetes or impaired glucose tolerance, an improvement in insulin sensitivity results in a decrease in plasma glucose concentrations (either fasting or after an oral glucose tolerance test or a meal). In a related manner, as regulated by the patient's pathophysiology, there will be an improvement in serum insulin concentrations in either the fasting state or after a glucose load or meal. These improvements in blood glucose control, should the subjects have type 2 diabetes, manifest as improvements in measures of long-term blood glucose control, such as, but not limited to, hemoglobin A1c (glycosylated hemoglobin) or fructosamine.        2. Blood pressure: It is believed that improvement in insulin sensitivity yields improvements in both systolic and diastolic blood pressure.        3. Lipids: Improvement in insulin resistance yields improvements in serum lipids, including, but not limited to, serum cholesterol and triglycerides.        4. Uric Acid: Improvement in insulin resistance yields improvements in serum uric acid.        5. Coagulation Factors: It is believed that improvement in insulin resistance restores normal factors that worsen the procoagulant state.        
cGMP PDE 9 inhibitors prevent the effect of the phosphodiesterase 9 enzyme that converts cGMP to inactive GMP thus increasing the amount of accumulated cGMP. This accumulation amplifies the vasodilatory, metabolic, and anti-atherogenic effects of the available nitric oxide and insulin. This amplification action mitigates the adverse effects associated with IRS and improve one or more of the associated conditions.
Diabetes mellitus is characterized by metabolic defects in production and utilization of carbohydrates, resulting in elevated blood glucose or hyperglycemia due to the failure to maintain appropriate blood sugar levels. Research in the treatment of diabetes has centered on attempts to normalize fasting and postprandial blood glucose levels. Current treatments include administration of exogenous insulin, oral administration of drugs and dietary therapies and exercise regimens.
Two major forms of diabetes mellitus are recognized. Type 1 diabetes, or insulin-dependent diabetes, is the result of an absolute deficiency of insulin, the hormone which regulates carbohydrate utilization. Type 2 diabetes, or non-insulin dependent diabetes, often occurs with normal, or even elevated levels of insulin and appears to be the result of the inability of tissues to respond appropriately to insulin. Complications of type 2 diabetes include retinopathy, nephropathy, neuropathy, and coronary heart disease, and are believed to be triggered by excessive protein glycation, which in turn results from excessive levels of circulating glucose. Reduction in hyperglycemia by treatment with a PDE9 inhibitor will lower the level of protein glycation and result in a diminution in these diabetic complications.
Polycystic ovary syndrome (PCOS) also known as Stein-Leventhal syndrome or functional ovarian hyperandrogenism, is a complex endocrine disorder associated with a long-term lack of ovulation (anovulation) and an excess of androgens (male sex hormones, e.g., testosterone) circulating in the blood. The disorder is characterized by the formation of cysts in the ovaries, a process related to the failure of the ovary to release an egg (ovum). In the majority of cases, the ovaries become enlarged. PCOS afflicts up to 22% of women during their childbearing years, although only 10% of these women develop symptoms. It is one of the most frequent causes of infertility in women.